Condensin I is required for faithful meiosis in Drosophila males

The heteropentameric condensin complexes play vital roles in the formation and faithful segregation of mitotic chromosomes in eukaryotes. While the different contributions of the two common condensin complexes, condensin I and condensin II, to chromosome morphology and behavior in mitosis have been thoroughly investigated, much less is known about the specific roles of the two complexes during meiotic divisions. In Drosophila melanogaster, faithful mitotic divisions depend on functional condensin I, but not on condensin II. However, meiotic divisions in Drosophila males require functional condensin II subunits. The role of condensin I during male meiosis in Drosophila has been unresolved. Here, we show that condensin I-specific subunits localize to meiotic chromatin in both meiosis I and II during Drosophila spermatogenesis. Live cell imaging reveals defects during meiotic divisions after RNAi-mediated knockdown of condensin I-specific mRNAs. This phenotype correlates with reduced male fertility and an increase in nondisjunction events both in meiosis I and meiosis II. Consistently, a reduction in male fertility was also observed after proteasome-mediated degradation of the condensin I subunit Barren. Taken together, our results demonstrate an essential role of condensin I during male meiosis in Drosophila melanogaster

Glatiramer acetate does not protect from acute ischemic stroke in mice

Background The role of the immune system in the pathophysiology of acute ischemic stroke is increasingly recognized. However, targeted treatment strategies to modulate immunological pathways in stroke are still lacking. Glatiramer acetate is a multifaceted immunomodulator approved for the treatment of relapsing-remitting multiple sclerosis. Experimental studies suggest that glatiramer acetate might also work in other neuroinflammatory or neurodegenerative diseases apart from multiple sclerosis. Findings We evaluated the efficacy of glatiramer acetate in a mouse model of brain ischemia/reperfusion injury. 60 min of transient middle cerebral artery occlusion was induced in male C57Bl/6 mice. Pretreatment with glatiramer acetate (3.5 mg/kg bodyweight) 30 min before the induction of stroke did not reduce lesion volumes or improve functional outcome on day 1. Conclusions Glatiramer acetate failed to protect from acute ischemic stroke in our hands. Further studies are needed to assess the true therapeutic potential of glatiramer acetate and related immunomodulators in brain ischemia

Molecular treatment effects of alemtuzumab in skeletal muscles of patients with IBM.

BACKGROUND: Mechanisms of inflammation and protein accumulation are crucial in inclusion body myositis (IBM). Recent evidence demonstrated that intravenous immunoglobulin failed to suppress cell-stress mediators in IBM. Here we studied the molecular changes in skeletal muscle biopsies from patients with IBM before and after treatment with alemtuzumab. METHODS: Relevant inflammatory and degeneration-associated markers were assessed by quantitative-PCR and immunohistochemistry in repeated muscle biopsy specimens from patients with IBM, which had been treated in a previously published uncontrolled proof-of-concept trial with alemtuzumab. RESULTS: There were no significant changes of the mRNA expression levels of the pro-inflammatory chemokines CXCL-9, CCL-4, and the cytokines IFN-γ, TGF-β, TNF-α, and IL-1β. Similarly, the degeneration-associated molecules ubiquitin, APP and αB-crystallin did not substantially change. Although no overall beneficial treatment effect was noted except for a 6-month stabilization, some patients experienced a transient improvement in muscle strength. In such responders, a trend towards reduced expression of inflammatory markers was noted. In contrast, the expression remained unchanged in the others who did not experience any change. The expression levels of IL-1β and MHC-I correlated with the positive clinical effect. By immunohistochemistry, some inflammatory mediators like CD8, CXCL-9, and MHC-I were downmodulated. However, no consistent changes were noted for ubiquitin, nitrotyrosin and β-amyloid. CONCLUSIONS: Alemtuzumab showed a trend towards downregulation of the expression of some inflammatory molecules in skeletal muscle of IBM patients but has no effect on several crucial markers of cell stress and degeneration. The data are helpful to explain the molecular treatment effects of future lymphocyte-targeted immunotherapies in IBM

COU254, a specific 3-carboxamide-coumarin inhibitor of coagulation factor XII, does not protect mice from acute ischemic stroke

Background: Anticoagulation is an important means to prevent from acute ischemic stroke but is associated with a significant risk of severe hemorrhages. Previous studies have shown that blood coagulation factor XII (FXII)- deficient mice are protected from pathological thrombus formation during cerebral ischemia without bearing an increased bleeding tendency. Hence, pharmacological blockade of FXII might be a promising and safe approach to prevent acute ischemic stroke and possibly other thromboembolic disorders but pharmacological inhibitors selective over FXII are still lacking. In the present study we investigated the efficacy of COU254, a novel nonpeptidic 3-carboxamide-coumarin that selectively blocks FXII activity, on stroke development and post stroke functional outcome in mice. Methods: C57Bl/6 mice were treated with COU254 (40 mg/kg i.p.) or vehicle and subjected to 60 min transient middle cerebral artery occlusion (tMCAO) using the intraluminal filament method. After 24 h infarct volumes were determined from 2,3,5-Triphenyltetrazoliumchloride(TTC)-stained brain sections and functional scores were assessed. Hematoxylin and eosin (H&E) staining was used to estimate the extent of neuronal cell damage. Thrombus formation within the infarcted brain areas was analyzed by immunoblot. Results: Infarct volumes and functional outcomes on day 1 after tMCAO did not significantly differ between COU254 pre-treated mice or untreated controls (p > 0.05). Histology revealed extensive ischemic neuronal damage regularly including the cortex and the basal ganglia in both groups. COU254 treatment did not prevent intracerebral fibrin(ogen) formation. Conclusions: COU254 at the given concentration of 40 mg/kg failed to demonstrate efficacy in acute ischemic stroke in this preliminary study. Further preclinical evaluation of 3-carboxamide-coumarins is needed before the antithrombotic potential of this novel class of FXII inhibitors can be finally judged

Report on the 1st scientific meeting of the "Verein zur Förderung des Wissenschaftlichen Nachwuchses in der Neurologie" (NEUROWIND e.V.) held in Mittenwalde/Motzen, Germany, Oct. 30th - Nov. 1st, 2009

Report on the 1st scientific meeting of the "Verein zur Forderung des Wissenschaftlichen Nachwuchses in der Neurologie" (NEUROWIND e.V.) held in Mittenwalde/Motzen, Germany, Oct. 30th - Nov. 1st, 2009 A scientific meeting repor

Report on the 3'rd scientific meeting of the "Verein zur Förderung des Wissenschaftlichen Nachwuchses in der Neurologie" (NEUROWIND e.V.) held in Motzen, Germany, Nov. 4'th - Nov. 6'th, 2011

From November 4th- 6th 2011, the 3rd NEUROWIND e.V. meeting was held in Motzen, Brandenburg, Germany. Like in the previous years, the meeting provided an excellent platform for scientific exchange and the presentation of innovative projects for young colleagues in the fields of neurovascular research, neuroinflammation and neurodegeneration. As kick-off to the scientific sessions, Reinhard Hohlfeld, Head of the Institute for Clinical Neuroimmunology in Munich, gave an illustrious overview on the many fascinations of neuroimmunologic research. A particular highlight on the second day of the meeting was the award of the 1’st NEUROWIND e.V. prize for young academics in the field of experimental neurology. This award is posted for young colleagues under the age of 35 with a significant achievement in the field of neurovascular research, neuroinflammation or neurodegeneration and comprises an amount of 20.000 Euro, founded by Merck Serono GmbH, Darmstadt. Germany. The first prize was awarded to Ivana Nikic from Martin Kerschensteiner’s group in Munich for her brilliant work on a reversible form of axon damage in experimental autoimmune encephalomyelitis and multiple sclerosis, published in Nature Medicine in 2011. This first prize award ceremony was a great incentive for the next call for proposals now upcoming in 2012

Thrombin-Activatable Fibrinolysis Inhibitor (TAFI) Deficient Mice Are Susceptible to Intracerebral Thrombosis and Ischemic Stroke

Background: Thrombus formation is a key step in the pathophysiology of acute ischemic stroke and results from the activation of the coagulation cascade. Thrombin plays a central role in this coagulation system and contributes to thrombus stability via activation of thrombin-activatable fibrinolysis inhibitor (TAFIa). TAFIa counteracts endogenous fibrinolysis at different stages and elevated TAFI levels are a risk factor for thrombotic events including ischemic stroke. Although substantial in vitro data on the influence of TAFI on the coagulation-fibrinolysis-system exist, investigations on the consequences of TAFI inhibition in animal models of cerebral ischemia are still lacking. In the present study we analyzed stroke development and post stroke functional outcome in TAFI(-/-) mice. Methodology/Principal Findings: TAFI(-/-) mice and wild-type controls were subjected to 60 min transient middle cerebral artery occlusion (tMCAO) using the intraluminal filament method. After 24 hours, functional outcome scores were assessed and infarct volumes were measured from 2,3,5- Triphenyltetrazoliumchloride (TTC)-stained brain slices. Hematoxylin and eosin (H&E) staining was used to estimate the extent of neuronal cell damage. Thrombus formation within the infarcted brain areas was analyzed by immunoblot. Infarct volumes and functional outcomes did not significantly differ between TAFI(-/-) mice and controls (p>0.05). Histology revealed extensive ischemic neuronal damage regularly including the cortex and the basal ganglia in both groups. TAFI deficiency also had no influence on intracerebral fibrin(ogen) formation after tMCAO. Conclusion: Our study shows that TAFI does not play a major role for thrombus formation and neuronal degeneration after ischemic brain challeng

Post-stroke inhibition of induced NADPH oxidase type 4 prevents oxidative stress and neurodegeneration

Ischemic stroke is the second leading cause of death worldwide. Only one moderately effective therapy exists, albeit with contraindications that exclude 90% of the patients. This medical need contrasts with a high failure rate of more than 1,000 pre-clinical drug candidates for stroke therapies. Thus, there is a need for translatable mechanisms of neuroprotection and more rigid thresholds of relevance in pre-clinical stroke models. One such candidate mechanism is oxidative stress. However, antioxidant approaches have failed in clinical trials, and the significant sources of oxidative stress in stroke are unknown. We here identify NADPH oxidase type 4 (NOX4) as a major source of oxidative stress and an effective therapeutic target in acute stroke. Upon ischemia, NOX4 was induced in human and mouse brain. Mice deficient in NOX4 (Nox4(-/-)) of either sex, but not those deficient for NOX1 or NOX2, were largely protected from oxidative stress, blood-brain-barrier leakage, and neuronal apoptosis, after both transient and permanent cerebral ischemia. This effect was independent of age, as elderly mice were equally protected. Restoration of oxidative stress reversed the stroke-protective phenotype in Nox4(-/-) mice. Application of the only validated low-molecular-weight pharmacological NADPH oxidase inhibitor, VAS2870, several hours after ischemia was as protective as deleting NOX4. The extent of neuroprotection was exceptional, resulting in significantly improved long-term neurological functions and reduced mortality. NOX4 therefore represents a major source of oxidative stress and novel class of drug target for stroke therapy